Lipid Metabolism-related Factors Research Articles

Diacylglycerol O-acyltransferase 2, a Novel Target of Flavivirus NS2B3 Protease, Promotes Zika Virus Replication by Regulating Lipid Droplet Formation.

Various lipid metabolism-related factors are essential for Zika virus (ZIKV) replication. In this study, we revealed a crucial role of diacylglycerol O-acyltransferase 2 (DGAT2) in ZIKV replication using a short hairpin RNA-based gene knockdown technique. The replication of ZIKV was significantly inhibited by DGAT2 depletion in multiple cell lines and restored by trans-complementation with DGAT2. Mechanistically, DGAT2 is recruited in the viral replication complex by interacting with non-structural (NS) proteins. Among them, both human and murine DGAT2s can be cleaved by NS2B3 at the 122R-R-S124 site. Interestingly, the cleavage product of DGAT2 becomes more stable and is sufficient to promote the lipid droplet (LD) formation independent of its enzymatic activity. This work identifies DGAT2 as a novel target of the viral protease NS2B3 and elucidates that DGAT2 is recruited by viral proteins into the replication complex, thereby playing a proviral role by promoting LD formation, which advances our understanding of host-flavivirus interaction.

Dynamic functional network connectivity and its association with lipid metabolism in Alzheimer's disease.

The study aims to examine the changing trajectory characteristics of dynamic functional network connectivity (dFNC) and its correlation with lipid metabolism-related factors across the Alzheimer's disease (AD) spectrum populations. Data from 242 AD spectrum subjects, including biological, neuroimaging, and general cognition, were obtained from the Alzheimer's Disease Neuroimaging Initiative for this cross-sectional study. The study utilized a sliding-window approach to assess whole-brain dFNC, investigating group differences and associations with biological and cognitive factors. Abnormal dFNC was used in the classification of AD spectrum populations by support vector machine. Mediation analysis was performed to explore the relationships between lipid-related indicators, dFNC, cerebrospinal fluid (CSF) biomarkers, and cognitive performance. Significant group difference concerning were observed in relation to APOE-ε4 status, CSF biomarkers, and cognitive scores. Two reoccurring connectivity states were identified: state-1 characterized by frequent but weak connections, and state-II characterized by less frequent but strong connections. Pre-AD subjects exhibited a preference for spending more time in state-I, whereas AD patients tended remain in state-II for longer periods. Group difference in dFNC was primarily found between AD and non-AD participants within each state. The dFNC of state-I yielded strong power to distinguish AD from other groups compared with state-II. APOE-ε4+, high polygenic score, and high serum lipid group were strongly associated with network disruption between association cortex system and sensory cortex system that characterized elevation of cognitive function, which may suggest a compensatory mechanism of dFNC in state-I, whereas differential connections of state-II mediated the relationships between APOE-ε4 genotype and CSF biomarkers, and cognitive indicators. The dysfunction of dFNC temporal-spatial patterns and increased cognition in individuals with APOE-ε4, high polygenic score, and higher serum lipid levels shed light on the lipid-related mechanisms of dynamic network reorganization in AD.

MTORC2 knockdown mediates lipid metabolism to alleviate hyperlipidemic pancreatitis through PPARα.

Hyperlipidemic pancreatitis (HP) is an inflammatory injury of the pancreas triggered by elevated serum triglyceride (TG) levels. The mechanistic target of rapamycin (mTOR) signaling pathway plays a crucial role in regulating lipid homeostasis and inflammation. This study aimed to investigate whether the activity of mTOR complex 2 (mTORC2) affects the progression of HP and its underlying mechanisms. In vivo, a high-fat diet and retrograde administration of sodium taurocholate were employed to establish theHP models in rats, with pancreatic tissue pathology evaluated. The expression of Rictor and peroxisome proliferator-activator receptor (PPAR) was examined. The serum levels of TG, fatty acid metabolites, inflammatory and lipid metabolism-related factors were determined. In vitro, pancreatic acinar cells (PACs) were exposed to palmitic acid and cholecystokinin-8. PAC apoptosis, pyroptosis, and ferroptosis were assessed. In the HP models, rats and PACs exhibited upregulated Rictor and downregulated PPARα, and Rictor knockdown promoted PPARα expression. In vivo, Rictor knockdown decreased the serum levels of TG, α-amylase, total cholesterol, low-density lipoprotein cholesterol, lactate dehydrogenase, and inflammatory factors, while increasing high-density lipoprotein cholesterol levels. Rictor knockdown increased ACOX1 and CPT1α and decreased SREBP-1, CD36, SCD1, ACLY, and ACACA. Rictor knockdown reduced damage to pancreatic tissue structure. In vitro, Rictor knockdown inhibited PAC apoptosis, pyroptosis, and ferroptosis. Treatment with the PPARα antagonist GW6471 abolished the beneficial effects of Rictor knockdown. Rictor/mTORC2 deficiency reduces serum TG levels, maintains lipid homeostasis, and suppresses inflammation by inhibiting PPARα expression. Weakening mTORC2 activity holds promise as a novel therapeutic strategy for HP.

Obesity and adiposity promote the development of non-suppurative otitis media: a Mendelian randomization study.

Observational studies have found that obesity is associated with the development of non-suppurative otitis media (NSOM), but the causality and pathogenesis are unclear. This study aimed to investigate the association between obesity, lipid metabolism, and NSOM at the genetic level. We performed a bidirectional two-sample Mendelian randomization (MR) study to examine the causal relationship between obesity, lipid metabolism-related factors, and NSOM by using the datasets obtained from the IEU Open genome-wide association studies (GWAS) Project. Furthermore, a multivariate MR (MVMR) analysis on lipid indicators was conducted to validate the results. We then used obesity or body mass index (BMI) as the exposure and NSOM as the outcome to search for possible mediators in lipids and adipokines. Using NSOM as the outcome, we found nine positive exposure results related to obesity and lipid metabolism. Among them, obesity, BMI, body fat percentage, waist circumference, hip circumference, and resistin were risk factors, while apolipoprotein A1 (apoA1), high-density lipoprotein cholesterol (HDL-C), and nerve growth factor (NGF) were protective factors. Then, we used the obesity and lipid metabolism-related factors as outcomes and NSOM as the exposure to perform the MR analysis, which failed to obtain positive results. In the MVMR analysis, we found that HDL cholesterol and apoA1 remained causally associated with NSOM after correction for other potential confounders. Simultaneously, when obesity or BMI was used as the exposure and NSOM as the outcome, HDL cholesterol or apoA1 served as mediators through a two-step MR analysis. The MR analysis for mediation, obesity, and BMI reduced the production of HDL or apoA1, which served as protective factors affecting the development of NSOM. At the genetic level, obesity and adiposity may promote the development of NSOM, while NSOM has no effect on obesity and adiposity. Obesity can also encourage the progress of NSOM by reducing HDL cholesterol/apoA1. Resistin may be a potential risk factor for NSOM, whereas NGF may be a potential protective factor.

Er-Dong-Xiao-Ke decoction regulates lipid metabolism via PPARG-mediated UCP2/AMPK signaling to alleviate diabetic meibomian gland dysfunction

Ethnopharmacological relevanceMeibomian gland dysfunction (MGD), complicated by type 2 diabetes, is associated with a high incidence of ocular surface disease, and no effective drug treatment exists. Diabetes mellitus (DM) MGD shows a notable disturbance in lipid metabolism. Er-Dong-Xiao-Ke decoction (EDXKD) has important functions in nourishing yin, clearing heat, and removing blood stasis, which are effective in the treatment of DM MGD. Aim of the studyTo observe the therapeutic effect of EDXKD on DM MGD and its underlying molecular mechanism. Materials and methodsAfter establishing a type 2 DM (T2DM)-induced MGD rat model, different doses of EDXKD and T0070907 were administered. The chemical constituents of EDXKD were identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and the molecular mechanism of EDXKD in treating DM MGD was predicted using network pharmacology. Lipid metabolism in DM meibomian glands (MGs) was analyzed using LC-MS/MS, and lipid biomarkers were screened and identified. Histological changes and lipid accumulation in MGs were detected by staining, and Peroxisome proliferator-activated receptor gamma (PPARG) expression in MG acinar cells was detected by immunofluorescence. The expression of lipid metabolism-related factors was detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) or western blotting. ResultsEDXKD reduced lipid accumulation in the MGs and improved the ocular surface index in DM MGD rats. The main active components of EDXKD had advantages in lipid regulation. Additionally, the PPARG signaling pathway was the key pathway of EDXKD in the treatment of DM MGD. Twelve lipid metabolites were biomarkers of EDXKD in the treatment of DM MGD, and glycerophospholipid metabolism was the main pathway of lipid regulation. Moreover, EDXKD improved lipid deposition in the acini and upregulated the expression of PPARG. Further, EDXKD regulated the PPARG-mediated UCP2/AMPK signaling network, inhibited lipid production, and promoted lipid transport. ConclusionEDXKD is an effective treatment for MGD in patients with T2DM. EDXKD can regulate lipids by regulating the PPARG-mediated UCP2/AMPK signaling network, as it reduced lipid accumulation in the MGs of DM MGD rats, promoted lipid metabolism, and improved MG function and ocular surface indices.

Correlation between the serum FABP4, ANGPTL3, and ANGPTL4 levels and coronary artery disease.

Lipid metabolism related factors, such as angiopoietin-like protein 3 (ANGPTL3), angiopoietin-like 4 (ANGPTL4), fatty acid-binding protein 4 (FABP4) are newly discovered factors that can affect coronary artery disease (CAD). In this study, we aimed to investigate the relationship between CAD and these lipid metabolism factors. ANGPTL3, ANGPTL4, and FABP4 may provide a new method for the control of CAD risk factors and the prevention and treatment of CAD. We enrolled 284 consecutive inpatients with suspected CAD and divided them into CAD and non-CAD groups based on the coronary angiography results. Serum ANGPTL3, ANGPTL4, FABP4, and tumor necrosis factor-α (TNF-α) levels were estimated using the enzyme-linked immunosorbent assay. Multivariate logistic regression was used to assess the risk factors for CAD. The receiver operating characteristic curve was used to determine the cutoff and diagnostic values. The serum TNF-α, FABP4, ANGPTL3, and ANGPTL4 values showed a significant difference between the CAD and non-CAD groups (p < .05). After adjusting for confounding factors, the FABP4, ANGPTL3, and ANGPTL4 levels were independently associated with CAD (p < .05). The ANGPTL3 expression level was an independent risk factor for CAD in patients with hypertension, but not in those without hypertension. The ANGPTL3 > 67.53 ng/mL, ANGPTL4 > 29.95 ng/mL, and FABP4 > 1421.25 ng/L combination had the highest diagnostic value for CAD. ANGPTL3, ANGPTL4, and FABP4 were identified as independent risk factors for CAD and have valuable clinical implications for the diagnosis and treatment of CAD.

Ilex paraguariensis A.St.-Hil. improves lipid metabolism in high-fat diet-fed obese rats and suppresses intracellular lipid accumulation in 3T3-L1 adipocytes via the AMPK-dependent and insulin signaling pathways.

Obesity is closely associated with several chronic diseases, and adipose tissue plays a major role in modulating energy metabolism. This study aimed to determine whether Mate, derived from I. paraguariensis A.St.-Hil., ameliorates lipid metabolism in 3T3-L1 adipocytes and high-fat diet (HFD)-fed obese Sprague-Dawley (SD) rats. 3T3-L1 adipocytes were cultured for 7 days, following which intracellular lipid accumulation and expression levels of lipid metabolism-related factors were examined. Dorsomorphin was used to investigate the potential pathways involved, particularly the adenosine monophosphate-activated protein kinase (AMPK)- dependent pathway. Mate was administered to rat HFD-fed obese SD models for 8 consecutive weeks. The expression of lipid metabolism-related factors in the organs and tissues collected from dissected SD rats was evaluated. Mate suppressed intracellular lipid accumulation in 3T3-L1 adipocytes, increased the protein and gene expression levels of AMPK, hormone sensitive lipase (HSL), calmodulin kinase kinase (CaMKK), liver kinase B1 (LKB1), protein kinase A (PKA), CCAAT/enhancer binding protein β (C/EBPβ), insulin receptor b (IRβ), and insulin receptor substrate 1 (IRS1) (Tyr465), and decreased those of sterol regulatory element binding protein 1C (Srebp1c), fatty acid synthase (FAS), peroxisome-activated receptor γ (PPARγ), and IRS1 (Ser1101). Furthermore, an AMPK inhibitor abolished the effects exerted by Mate on intracellular lipid accumulation and HSL and FAS expression levels. Mate treatment suppressed body weight gain and improved serum cholesterol levels in HFD-fed obese SD rats. Treatment with Mate increased the protein and gene expression levels of AMPK, PKA, Erk1/Erk2 (p44/p42), and uncoupling protein 1 and reduced those of mammalian target of rapamycin, S6 kinase, Srebp1c, ap2, FAS, Il6, Adiponectin, Leptin, and Fabp4 in rat HFD-fed obese SD models. Mate suppressed intracellular lipid accumulation in 3T3-L1 adipocytes and improved lipid metabolism in the epididymal adipose tissue of HFD-fed obese SD rats via the activation of AMPK-dependent and insulin signaling pathways.

Pollution Characteristics of Different Components of PM2.5 in Taiyuan during 2017–2020 Wintertime and Their Toxicity Effects on HepG2 Cells

Fine particulate matter (PM2.5) is a common pollutant, and its health risk has attracted much attention. Studies have shown that PM2.5 exposure is associated with liver disease. The composition of PM2.5 is complex, and its hepatotoxic effects and lipid metabolism process are not well understood. In this study, we detected the concentrations of PM2.5 and its components (metals and polycyclic aromatic hydrocarbon (PAHs)) in the winter in Taiyuan, Shanxi Province, China, from 2017 to 2020 and then assessed the health risks. We also investigated the effects of different components (whole particles (WP), water-soluble particles (WSP), organic particles (OP)) of PM2.5 on the cytotoxicity and lipid metabolism in human liver cell line (HepG2) after 24 h of treatment. The changes in cytotoxicity indexes (LDH, IL-6, reactive oxygen species (ROS)) and lipids (triglyceride (TG), free fatty acid (FFA)) were measured after 24 h. The mRNA expression of lipid metabolism-related factors (SREBP1, CD36, MTTP) was determined by real-time quantitative RT-qPCR. Finally, the correlation between metals and PAHs with higher PM2.5 content in 4 years and biomarkers was analyzed. The results showed that: (1) The PM2.5 pollution was severe in Taiyuan during winter in 2017 and the subsequent four years. The calculation results of the metal enrichment factor (EF) value and PAHs characteristic ratio of PM2.5 showed that PM2.5 pollution sources differed in different years. (2) Exposure to metals and PAHs in PM2.5 did not cause a non-carcinogenic risk. Metals had no cancer risk, while PAHs inhaled in PM2.5 in 2017 and 2018 had a potential cancer risk. The atmospheric PM2.5 pollution in Taiyuan has had a downward trend, but the PAHs in the PM2.5 of 2017–18, when the pollution is relatively serious, have a potential carcinogenic risk. (3) WP, OP and WSP inhibited cell survival rate from 2017 to 2020, and OP had higher cytotoxicity at the same concentration. (4) WP, OP and WSP increased the levels of LDH, IL-6, TNF-α, ROS, MDA, TG and FFA, and inhibited SOD activity in a dose-effect relationship. The organic components in PM2.5 are more toxic to HepG2 cells and affect the expression of lipid metabolism-related factors at the transcriptional level. (5) The mRNA expressions of factors related to lipid synthesis, uptake, oxidation and output were up-regulated after treatment with PM2.5 and its components, suggesting a lipid metabolism disorder. (6) The biomarkers were associated with certain metals (Zn, Pb, Cu and Cr) and PAHs in PM2.5. These suggested that PM2.5- and PM2.5-bound organic matter caused HepG2 cytotoxicity and affected lipid metabolism.

The association of lipid metabolism and sarcopenia among older patients: a cross-sectional study

Sarcopenia has become a heavy disease burden among the elderly. Lipid metabolism was reported to be involved in many degenerative diseases. This study aims to investigate the association between dysregulated lipid metabolism and sarcopenia in geriatric inpatients. This cross-sectional study included 303 patients aged ≥ 60, of which 151 were diagnosed with sarcopenia. The level of total cholesterol (TC), triglyceride (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), homocysteine (HCY), BMI, and fat percentage, were compared between sarcopenia and non-sarcopenia patients. The Spearman correlation coefficient was used to estimate the association between sarcopenia and the level of lipid metabolism. To determine risk factors related to sarcopenia, a multivariate logistic regression analysis was carried out. Risk prediction models were constructed based on all possible data through principal component analysis (PCA), Logistic Regression (LR), Support Vector Machine (SVM), k-Nearest Neighbor (KNN), and eXtreme Gradient Boosting (XGboost). We observed rising prevalence of sarcopenia with increasing age, decreasing BMI, and fat percentage (p < 0.001, Cochran Armitage test). Multivariate logistic regression analysis revealed sarcopenia’s risk factors, including older age, male sex, lower levels of BMI, TC, and TG, and higher levels of LDL and HCY (p < 0.05). The sarcopenia risk prediction model showed the risk prediction value of sarcopenia, with the highest area under the receiver operating curve (AUC) of 0.775. Our study provided thorough insight into the risk factors associated with sarcopenia. It demonstrated that an increase in lipid metabolism-related parameters (BMI, TG, TC), within normal reference ranges, may be protective against sarcopenia. The present study can illuminate the direction and significance of lipid metabolism-related factors in preventing sarcopenia.

Isorhynchophylline improves lipid metabolism disorder by mediating a circadian rhythm gene Bmal1 in spontaneously hypertensive rat.

Hypertension is a progressive metabolic disease characterized by circadian regulation of lipid metabolism disorder. Identifying specific lipid components and maintaining circadian homeostasis of lipid metabolism might be a promising therapeutic strategy for hypertension. Isorhynchophylline (IRP) can regulate lipid metabolism; however, the underlying mechanism of IRP in improving lipid metabolism rhythm disorder is still unclear. The lipid circadian biomarkers and abnormal metabolic pathways intervened by IRP were investigated using diurnal lipidomic research methods. The 24-h circadian changes in mRNA and protein expression levels of circadian genes, including Bmal1, Clock, Cry1, Cry2, Per1, and Per2, and lipid metabolism-related factors (PPARα and LPL) were determined using RT-PCR and western blot analyses, respectively. The underlying mechanisms were intensively investigated by inhibiting Bmal1. Molecular docking and drug affinity responsive target stability analyses were performed to assess the binding affinity of IRP and Bmal1. IRP treatment could effectively improve 24-h blood pressure, ameliorate the lipid metabolic rhythm disorder, reverse the expression levels of circadian rhythm genes, and regulate lipid metabolism-related genes (PPARα and LPL) by mediating Bmal1. This study highlighted the potential effects of IRP in maintaining the circadian homeostasis of lipid metabolism and the treatment of hypertension.

Application of systemic inflammation indices and lipid metabolism-related factors in coronary artery disease.

We aimed to investigate the relationship between coronary artery disease (CAD) and systemic inflammation indices and lipid metabolism-related factors and subsequently, discuss the clinical application of these factors in CAD. We enrolled 284 consecutive inpatients with suspected CAD and divided them into a CAD group and a non-CAD group according to coronary angiography results. Serum levels of angiopoietin-like protein 3 (ANGPTL3), angiopoietin-like protein 4 (ANGPTL4), fatty acid-binding protein 4 (FABP4), and tumor necrosis factor-α (TNF-α) levels were assessed using the ELISA and the systemic inflammation indices were calculated. Multivariate logistic regression was used to assess the risk factors of CAD. The receiver operating characteristic curve was used to determine the cutoff and diagnostic values. The neutrophil-to-high density lipoprotein cholesterol ratio (5.04 vs. 3.47), neutrophil-to-lymphocyte ratio (3.25 vs. 2.45), monocyte-to-high density lipoprotein cholesterol ratio (MHR) (0.46 vs. 0.36), monocyte-to-lymphocyte ratio (0.31 vs. 0.26), systemic immune-inflammation index (SII) (696.00 vs. 544.82), serum TNF-α (398.15 ng/l vs. 350.65 ng/l), FABP4 (1644.00 ng/l vs. 1553.00 ng/l), ANGPTL3 (57.60 ng/ml vs. 52.85 ng/ml), and ANGPTL4 (37.35 ng/ml vs. 35.20 ng/ml) values showed a significant difference between the CAD and non-CAD groups ( P < 0.05). After adjusting for confounding factors, the following values were obtained: ANGPTL3 > 67.53 ng/ml [odds ratio (OR) = 8.108, 95% confidence interval (CI) (1.022-65.620)]; ANGPTL4 > 29.95 ng/ml [OR = 5.599, 95% CI (1.809-17.334)]; MHR > 0.47 [OR = 4.872, 95% CI (1.715-13.835)]; SII > 589.12 [OR = 5.131, 95% CI (1.995-13.200)]. These factors were found to be independently associated with CAD ( P < 0.05). Diabetes combined with MHR > 0.47, SII > 589.12, TNF-α >285.60 ng/l, ANGPTL3 > 67.53 ng/ml, and ANGPTL4 > 29.95 ng/l had the highest diagnostic value for CAD [area under the curve: 0.921, 95% CI, (0.881-0.960), Sensitivity: 88.9%, Specificity: 82.2%, P < 0.001]. MHR > 0.47, SII > 589.12, TNF-α >285.60 ng/l, ANGPTL3 > 67.53 ng/ml, and ANGPTL4 > 29.95 ng/l were identified as independent CAD risk factors and have valuable clinical implications in the diagnosis and treatment of CAD.

Extraction of Naringin from Pomelo and Its Therapeutic Potentials against Hyperlipidemia.

Pomelo peel is a natural plant product with numerous pharmacological effects and is used in traditional Chinese medicine. In the present study, we extracted naringin from pomelo peel and aimed to decipher its therapeutic potential against hyperlipidemia. We used ultrasonic-assisted extraction to obtain naringin prior to identifying its structure, to evaluate its ability in binding sodium glycine cholate and sodium bovine cholate in vitro by simulating the gastrointestinal environment, so as to evaluate its blood lipid-lowering activity. The hyperlipidemia mouse model was established. Following the intragastric administration of naringin for 5 weeks, we measured the weight change, organ index, high-density lipoprotein cholesterol (HDL-C), serum total cholesterol (TC), serum triglycerides (TG), liver superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), low-density lipoprotein cholesterol (LDL-C) level, malondialdehyde (MDA), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) level of mice in the normal control and high-fat diet groups in addition to the high-, medium-, and low-dose naringin groups. The pathological changes in the liver were observed under a light microscope. The total RNA of the liver was extracted, and the mRNA expression level of lipid metabolism-related factors in mouse liver was detected via a fluorescence quantitative polymerase chain reaction (PCR). Naringin significantly (p &lt; 0.01) reduced the body weight, organ index, serum TG, LDL-C, and TC levels of hyperlipidemic mice, but increased the serum HDL-C levels (p &lt; 0.01). Furthermore, naringin increased GSH Px and SOD activity (p &lt; 0.01), while decreasing MDA, ALT, and AST levels, as well as the liver index (p &lt; 0.01). There was no statistically significant difference in the brain, heart, spleen, kidney, and other indicators (p &gt; 0.05). A histopathological analysis of mouse liver showed that naringin could alleviate the degenerative damage of fatty liver cells in hyperlipidemic mice. Naringin could significantly (p &lt; 0.01) reduce the expression of FAS and SREBP-1c mRNA, and simultaneously increase PPARα mRNA expression. This study shows that naringin has the strong effect of lowering lipids and protecting the liver in hyperlipidemic mice. Our findings underscore the anti-hyperlipidemia potential of naringin and increase the scientific understanding of its anti-hyperlipidemia effects, that may lead to its potential application as a dietary strategy for hyperlipidemia management in the future.

Genistein activated SIRT1-AMPK signaling pathway mediated by ERβ-FOXO1-Nampt to reduce fat accumulation in chicken hepatocytes

Excessive fat accumulation in broiler chickens would seriously threaten the poultry industry. It leads to lower feed conversion rate and worse meat quality. Even worse, it harms the consumers' health due to the intake of high-fat chicken products. Dietary supplements with bioactive ingredients have been considered an effective way to solve this problem. Genistein is the primary phytoestrogen in soybean. Its fat-reduction effect has been reported, but the molecular mechanism is unclear. The present study found that genistein reduced lipid droplets accumulation by regulating lipid metabolism-related factors expression in chicken hepatocytes. The research showed that genistein significantly increased phosphor (p)-AMP-activated protein kinase (p-AMPK) and Sirtuin 1 (SIRT1) protein expressions. The effect of genistein on reducing lipid droplets accumulation and upregulating p-AMPK protein level was blocked entirely when pretreated with SIRT1 inhibitor. These results implied that SIRT1 is required to activate AMPK. Furthermore, genistein treatment significantly upregulated the SIRT1 protein level when pretreated with AMPK inhibitor. We demonstrated that the activation of estrogen receptor β-Forkhead box O1-Nicotinamide phosphoribosyl transferase (ERβ-FOXO1-Nampt) signaling pathway upregulated the NAD+ concentration in hepatocytes, and activated SIRT1 ultimately. In summary, we demonstrated that genistein suppressed lipid droplets accumulation in chicken hepatocytes by activating SIRT1-AMPK. The SIRT1-AMPK signaling pathway was mediated by ERβ-FOXO1-Nampt. These findings increase our understanding of the mechanisms of genistein on fat reduction, and provide compelling evidence for it as a nutritional supplement to prevent excessive fat deposition and lipid metabolism-related diseases in animals and even humans.

Ramulus Mori (Sangzhi) Alkaloids Ameliorate Obesity-Linked Adipose Tissue Metabolism and Inflammation in Mice

Obesity has become a global epidemic disease as it is closely associated with a chronic low-grade inflammatory state that results in metabolic dysfunction. Ramulus Mori (Sangzhi) alkaloids (SZ-A) derived from Morus alba L. were licensed to treat type 2 diabetes (T2DM) in 2020. In this study, we explored the effect of SZ-A on adipose tissue metabolism and inflammation using an obesity model induced by a high-fat diet (HFD). C57BL/6J mice were fed high fat for 14 weeks and followed by SZ-A 400 mg/kg treatment via gavage for another six weeks, during which they were still given the high-fat diet. The results showed that SZ-A notably reduced body weight and serum levels of lipid metabolism-related factors, such as triglycerides (TG) and total cholesterol (TC); and inflammation-related factors, namely tumor necrosis factor alpha (TNFα), interleukin 6 (IL6), fibrinogen activator inhibitor-1 (PAI-1), angiopoietin-2 (Ang-2), and leptin (LEP), in the HFD-induced mice. SZ-A increased the protein and mRNA expression of lipid metabolism-related factors, including phosphorylated acetyl coenzyme A carboxylase (p-ACC), phosphorylated hormone-sensitive triglyceride lipase (p-HSL), adipose triglyceride lipase (ATGL), and peroxisome proliferator-activated receptor-alpha (PPARα), in adipose tissue. Immunohistochemistry results demonstrated that SZ-A significantly reduced the infiltration of pro-inflammatory M1-type macrophages in epididymal fat. The data also suggested that SZ-A down-regulates the transcriptional levels of inflammatory factors Il6, Tnfα, monocyte chemoattractant protein-1 (Mcp1), and F4/80, and up-regulates interleukin 4 (Il4), interleukin 10 (Il10), and interleukin 13 (Il13) in adipose tissue. Overall, the results indicate that SZ-A exhibits potential in regulating lipid metabolism and ameliorating obesity-linked adipose inflammation.

Piperine Improves Lipid Dysregulation by Modulating Circadian Genes Bmal1 and Clock in HepG2 Cells.

Metabolic disorders are closely associated with the dysregulation of circadian rhythms. Many bioactive components with lipid metabolism-regulating effects have been reported to function through circadian clock-related mechanisms. As the main pungent principle of black pepper, piperine (PIP) has been demonstrated to possess anti-obesity bioactivity by affecting hepatic lipid metabolism-related factors. However, whether the circadian clock genes Bmal1 and Clock are involved in the protective effect of PIP against lipid metabolism disorders remains unknown. In this work, oleic acid (OA) induced lipid accumulation in HepG2 cells. The effect of PIP on redox status, mitochondrial functions, and circadian rhythms of core clock genes were evaluated. Results revealed that PIP alleviated circadian desynchrony, ROS overproduction, and mitochondrial dysfunction. A mechanism study showed that PIP could activate the SREBP-1c/PPARγ and AMPK/AKT-mTOR signaling pathways in a Bmal1/Clock-dependent manner in HepG2 cells. These results indicated that Bmal1 and Clock played important roles in the regulating effect of PIP on hepatic lipid homeostasis.

Crocin ameliorates atherosclerosis by promoting the reverse cholesterol transport and inhibiting the foam cell formation via regulating PPARγ/LXR-α

ABSTRACT Crocin (CRO) is feasible in alleviating atherosclerosis (AS), the mechanism of which was therefore explored in the study. High-fat diet (HFD)-induced apolipoprotein E-deficient (ApoE−/−) mice and lysophosphatidic acid (LPA)-treated macrophages received CRO treatment. Treated macrophage viability was determined via MTT assay. In both murine and macrophage, the lipid level and total Cholesterol/Cholesteryl l Ester (TC/CE) levels were quantified by oil-red-O staining and ELISA, respectively. Lipid droplet, aortic plaque formation and collagen deposition were detected via Oil-red-O staining, hematoxylin–eosin staining and Masson staining, respectively. Liver X Receptor-α (LXR-α), Peroxisome Proliferator-Activated Receptor γ (PPARγ), CD68, PCSK9, CD36, ATP Binding Cassette Subfamily A Member 1 (ABCA1), phosphorylated (p)-AKT, and AKT expressions were detected via Western blot, the former three also being detected using Immunohistochemistry and the first being measured by qRT-PCR. CRO decreased HFD-induced weight gain, ameliorated the abnormal serum lipid levels of HFD-treated mice, and inhibited aortic plaque formation and lipid deposition, and increased collagen fibers, with upregulated high-density lipoprotein-cholesterol (HDL-C) and downregulated TC and low-density lipoprotein-cholesterol (LDL-C). CRO alleviated the HFD-induced upregulations of CD68, PCSK9 and CD36 as well as downregulations of PPARγ/LXR-α, ABCA1 and AKT phosphorylation. In LPA-treated macrophages, CRO alone exerted no effect on the viability yet inhibited the lipid droplets formation and downregulated TC/CE levels. Silent LXR-α reversed the effect of CRO on the lipid droplets formation and levels of lipid metabolism-related factors. CRO ameliorated AS by inhibiting foam cells formation and promoting reverse cholesterol transport via PPARγ/LXR-α.

Zonarol Protected Liver from Methionine- and Choline-Deficient Diet-Induced Nonalcoholic Fatty Liver Disease in a Mouse Model.

Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases with no approved treatment. Zonarol, an extract from brown algae, has been proven to have anti-inflammatory and antioxidant effects. In this study, we investigated the role of zonarol in the progression of methionine- and choline-deficiency (MCD) diet-induced NAFLD in mice. After oral treatment with zonarol, a lighter body weight was observed in zonarol group (ZG) mice in comparison to control group (CG) mice. The NAFLD scores of ZG mice were lower than those of CG mice. Hepatic and serum lipid levels were also lower in ZG mice with the reduced expression of lipid metabolism-related factors. Furthermore, ZG mice showed less lipid deposition, less inflammatory cell infiltration and lower inflammatory cytokine levels in comparison to CG mice. Moreover, the numbers of 8-hydroxy-20-deoxyguanosine (8-OHdG)-positive hepatocytes and levels of hepatic and serum thiobarbituric acid reactive substances (TBARS) were significantly lower in comparison to CG mice. The expression levels of nuclear factor erythroid 2 related factor 2 (Nrf2), as well as its upstream and downstream molecules, changed in ZG mice. Zonarol could prevent the progression of NAFLD by decreasing inflammatory responses, oxidative stress and improving lipid metabolism. Meanwhile the Nrf2 pathway may play an important role in these effects.

Hypothalamic Overexpression of Neurosecretory Protein GL Leads to Obesity in Male C57BL/6J Mice

Introduction: The mechanisms underlying obesity are not fully understood, necessitating the creation of novel animal models for the investigation of metabolic disorders. We have previously found that neurosecretory protein GL (NPGL), a newly identified hypothalamic neuropeptide, is involved in feeding behavior and fat accumulation in rats. However, the impact of NPGL on obesity remains unclear in any animal model. The present investigation sought to elucidate whether NPGL causes obesity in the obesity-prone mouse strain C57BL/6J. Methods: We overexpressed the NPGL-precursor gene (Npgl) in the hypothalamus using adeno-associated virus in male C57BL/6J mice fed normal chow (NC) or a high-calorie diet (HCD). After 9 weeks of Npgl overexpression, we measured adipose tissues, muscle, and several organ masses in addition to food intake and body mass. To assess the effects of Npgl overexpression on peripheral tissues, we analyzed mRNA expression of lipid metabolism-related genes by quantitative RT-PCR. Whole body energy consumption was assessed using an O₂/CO₂ metabolism measurement before an apparent increase in body mass. Results: Npgl overexpression increased food intake, body mass, adipose tissues and liver masses, and food efficiency under both NC and HCD, resulting in obesity observable within 8 weeks. Furthermore, we observed fat accumulation in adipose tissues and liver. Additionally, mRNA expression of lipid metabolism-related factors was increased in white adipose tissue and the liver after Npgl overexpression. Npgl overexpression inhibited energy expenditure during a dark period. Conclusion: Taken together, the present study suggests that NPGL can act as an obesogenic factor that acts within a short period of time in mice. As a result, this Npgl overexpression-induced obesity can be widely applied to study the etiology of obesity from genes to behavior.

Ablation of Selenbp1 Alters Lipid Metabolism via the Pparα Pathway in Mouse Kidney.

Selenium-binding protein 1 (Selenbp1) is a 2,3,7,8-tetrechlorodibenzo-p-dioxin inducible protein whose function is yet to be comprehensively elucidated. As the highly homologous isoform, Selenbp2, is expressed at low levels in the kidney, it is worthwhile comparing wild-type C57BL mice and Selenbp1-deficient mice under dioxin-free conditions. Accordingly, we conducted a mouse metabolomics analysis under non-dioxin-treated conditions. DNA microarray analysis was performed based on observed changes in lipid metabolism-related factors. The results showed fluctuations in the expression of numerous genes. Real-time RT-PCR confirmed the decreased expression levels of the cytochrome P450 4a (Cyp4a) subfamily, known to be involved in fatty acid ω- and ω-1 hydroxylation. Furthermore, peroxisome proliferator-activated receptor-α (Pparα) and retinoid-X-receptor-α (Rxrα), which form a heterodimer with Pparα to promote gene expression, were simultaneously reduced. This indicated that reduced Cyp4a expression was mediated via decreased Pparα and Rxrα. In line with this finding, increased levels of leukotrienes and prostaglandins were detected. Conversely, decreased hydrogen peroxide levels and reduced superoxide dismutase (SOD) activity supported the suppression of the renal expression of Sod1 and Sod2 in Selenbp1-deficient mice. Therefore, we infer that ablation of Selenbp1 elicits oxidative stress caused by increased levels of superoxide anions, which alters lipid metabolism via the Pparα pathway.

트레드밀 운동이 난소 절제 쥐의 지질대사 조절인자 및 지방조직 갈색화에 미치는 영향

The purpose of this study was to investigate the effects of aerobic exercise training on lipid metabolism regulators and browning of adipose tissue in ovariectomized rats. A total 36 of female Sprague-Dawley rats were divided into three groups: CON (normal control, n=12), OVA-CON (ovariectomized-control), OVA-TE (ovariectomized + treadmill exercise, n=12). The rats in the OVA-TE group were forced to run a treadmill for 30 min 4 times per week for 12 weeks. In the liver, the mRNA levels of peroxisome proliferator-activated receptor-gamma (PPARγ) and SPEBP-1 were significantly decreased in the OVA-TE group compared with the OVA-CON group (p<.05). In the gastrocnemius, the PGC-1α mRNA expression was significantly increased in the OVA-TE group compared to the OVACON group(p<.05). Also, the OVA-CON group showed significantly decreased UCP-1 mRNA levels compared to the CON group, while the OVA-TE group was significantly higher than the OVA-CON group(p<.05). These results indicate that regular aerobic exercise could improve the lipid metabolism-related factors and enhance the browning of adipose tissue in the ovariectomized rats.